Related Experiment Video
Updated: May 22, 2025
Investigating the Protective Effects of Platycodin D on Non-Alcoholic Fatty Liver Disease in a Palmitic Acid-Induced In Vitro Model
Published on: December 2, 2022
The Patatin-Like Phospholipase Domain-Containing 3 148M Variant Exacerbates Alcohol-Induced Liver Injury and
Jung-Hyo Cho1, Hyeong-Geug Kim2, Menghao Huang3
1Department of Biochemistry and Molecular Biology, School of Medicine, Indiana University, Indianapolis, Indiana; Department of East and West Cancer Center, Daejeon Korean Medicine Hospital of Daejeon University, Daejeon, Republic of Korea.
Abstract:
The patatin-like phospholipase domain-containing 3 (PNPLA3) protein 148M variant is strongly associated with cirrhosis and hepatocellular carcinoma (HCC). However, the underlying mechanisms remain elusive. This study aimed to elucidate the role of the PNPLA3148M variant in alcohol-related HCC development. Control and humanized PNPLA3148M transgenic mice were fed with an ethanol-containing diet for 12 weeks and examined for liver tumors. After the alcohol feeding, the PNPLA3148M mice had twofold higher liver cancer incidence rates and larger tumor sizes than the control mice. Cancer stem cell markers in the PNPLA3148M mouse livers were elevated relative to those in the control mouse livers. Alcohol detoxification was impaired in the PNPLA3148M mouse livers. Hepatic oxidative stress and DNA damage were elevated in the PNPLA3148M mice. Wnt/β-catenin and Yes-associated protein (YAP) and WW domain-containing transcription regulator 1 (WWTR1/TAZ) were activated in the PNPLA3148M mouse livers. The data suggest that the PNPLA3148M variant had a strong interaction with alcohol in HCC development through attenuation of alcohol detoxification and promotion of oncogenic pathways. Targeting the PNPLA3148M variant might be useful for the prevention or treatment of alcohol-associated HCC in patients carrying this variant.
